Formulation of newly developed drug entities that are poorly soluble is a challenging problem confronted by pharmaceutical researchers. A promising approach of overcoming such solubility factors resulting in bioavailability problems is the production of 'Nanocrystals'. In this article, production of drug nanocrystals by bottom up techniques (precipitation technique) and top down techniques (pearl milling, high pressure homogenisation) are reviewed. Special features of nanocrystals such as increased saturation solubility and dissolution velocity and characterisation parameters are discussed.
The current scenario of combinatorial chemistry, biology and genetics has given a thrust for development of newer drug candidates. Since the cell membrane is phospholipidic in nature, a drug candidate must possess a certain degree of lipophilicity to get absorbed through the intestinal wall after oral administration and also to exert its pharmacological action in the target tissue. High lipophilicity is advantageous in terms of permeability but leads to poor aqueous solubility. For drug absorption to occur, the drug must first be released from the dosage form, dissolve in gastrointestinal lumen contents before permeating across the intestinal epithelium. Based on this concept of permeability and solubility, drugs are classified in to BCS Class I, II, III and IV. Thus drugs with high permeability and poor water solubility (BCS Class II drugs) may not be adequately absorbed.
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The number of poorly soluble drugs emerging from drug discovery and development programs has steadily increased over the last ten years. Estimates state that 40% of the drugs in the development pipelines have solubility problems and about 60% of all drugs coming directly from synthesis are poorly soluble (Speiser, 1998; Merisko & Liversidge, 2002)
Typical problems associated with poorly soluble drugs are a too low bioavailability and/or erratic absorption. Thus pharmaceutical scientists are perpetually looking for new innovative formulation approaches to make these poorly soluble molecules bioavailable on per oral administration. In case of a significantly low bioavailability after oral administration, parenteral administration is not an alternate since this route cannot solve the problem in many cases. Intravenous injection as a solution is not possible because of poor solubility and even parenteral administration as a micronized product, either intramuscularly or intraparetoneally does not lead to sufficiently high drug levels because of too low solute volume at the injection site. Low saturation solubility combined with a low dissolution velocity prevents high blood levels (Muller et al., 2001).
Approaches to increase the saturation solubility involve solubility enhancement by solvent mixtures (e.g. ethanol-water), solubilization (e.g. mixed micelles as in Valium MM for i.v. injection) and complexation (e.g. addition of poly-ethylenglycol (PEG) or use of cyclodextrins). The limited success of these formulation approaches is demonstrated by the less products on the pharmaceutical market based on these principles.
A classical formulation approach for poorly soluble drugs is micronization of drug powders to sizes between 1 and 10 Î¼m to increase the surface area, and hence the dissolution velocity, but it does not lead to a sufficiently high bioavailability of many very poorly soluble drugs belonging to BCS Class II. Consequently, the next step was to move from micronization to nanonization. Since the beginning of the 90's, Elan Nanosystems (San Francisco,CA, USA) propagated the use of nanocrystals instead of microcrystals for oral bioavailability enhancement, but also to use nanocrystals suspended in water (nanosuspensions) for intravenous or pulmonary drug delivery.
Drug nanocrystals are crystals of nanometer size range, which means they are nanoparticles with a crystalline character. Based on the size unit, in the pharmaceutical area, nanoparticles should be deï¬ned as having a size between a few nanometers and 1000 nm. Drug nanocrystals are composed of 100% drug; without any carrier material. Dispersion of drug nanocrystals in liquid media is called "nanosuspension" and the dispersed particles need to be stabilized by surfactants or polymeric stabilizers. Dispersion media can be water, aqueous solutions or nonaqueous media (eg, liquid polyethylene glycol, oils) (Junghanns & Müller, 2008).
Theoretical considerations for increased solubility/ dissolution
Reducing the particles sizes from microns to nano level caused increased solubility and/ or dissolution. This increased dissolution velocity and thus increased bioavailability are due to any of the following changes in the physico-chemical character of drug:
Increase in surface area
The size reduction increases the surface area leading to an increased dissolution velocity as discussed by Brunner (1904); Nernst (1904) and Noyes-Whitney equation (1897) :
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where, dx/dt is dissolution rate, Xd is amount dissolved, A is particle surface area, D is diffusion coefficient, V represents volume of fluid available for dissolution, Cs is saturation solubility and h is effective boundary layer thickness.
Thus micronization enhances the bioavailability of drugs where the dissolution velocity is the rate limiting step. By moving from micronization to nanonization, the particle surface is further increased and thus the dissolution velocity also increases. In most cases, a low dissolution velocity is correlated with low saturation solubility.
Increase in saturation solubility
The saturation solubility (Cs) is a compound specific constant depending on the dissolution medium and the temperature. In case of polymorphism, the saturation solubility also depends on the crystalline structure which means highest solubility is exhibited by polymorph characterised by highest energy and lowest melting point. However, below a critical size of 1-2 Î¼m, the saturation solubility is also a particle size dependent as it increases with decreasing particle size below 1000 nm. Therefore, drug nanocrystals possess increased saturation solubility. This has two effects:
1. According to Noyes and Whitney (1897), the dissolution velocity increases because dx/dt is proportional to the concentration gradient (Cs - Cb)/h.
where, Cs and Cb is saturation solubility and bulk concentration, respectively and h is diffusional distance.
2. Due to the increased saturation solubility the concentration gradient between gut lumen and blood is increased, thus accelerating the absorption by passive diffusion (Junghanns & Müller, 2008).
Another pronounced feature of nanoparticles is the distinct increased adhesiveness compared to microparticles. The adhesiveness of the particles to the gut wall, a general characteristic of nanoparticle (Duchene & Ponchel, 1997), can be considered as another element improving the oral absorption of poorly soluble drugs apart from the increased saturation solubility and dissolution velocity.
The good physical stability of nanosuspensions is mainly reï¬‚ected by the absence of aggregation and Ostwald ripening phenomenon (Peters & Muller, 1996). The particles in the highly dispersed systems tend to grow, due to differences in saturation solubility in the vicinity of different sized particles the phenomenon is called Ostwald ripening (Jacobs et al., 2000). The solute concentration is higher in the vicinity of the smaller particles than that of the larger ones because of the higher saturation solubility of the small particles leading to diffusion of the molecules from the surrounding of the small particles to the surrounding of the large particles driven by the concentration gradient and their recrystallization on the surface of the larger particles. The continual dissolution of the small particles and recrystallization of the solute on the surface of the large particles lead to the formation of the microparticles. The lack of Ostwald ripening in nanosuspensions is attributed to their uniform particle size (Mantzaris, 2005). The absence of differently sized particles in nanosuspensions prevents the existence of the different saturation solubilities and concentration gradients in the vicinity of differently sized particles, which in turn prevents the Ostwald ripening effect.
Improved biological performance
An increase in the dissolution velocity and saturation solubility of a drug leads to an improvement in the in vivo performance of the drug irrespective of the route used.
Production of nanocrystals:
The techniques employed for the production of drug nanocrystals are classiï¬ed as ''bottom up'' methods and ''top down'' methods (Xing, 2004). The ''bottom up'' methods, like the precipitation technique, involve the construction of nanocrystals from the molecules and the ''top down'' methods, like the pearl milling and homogenization techniques, involve the formation of the nanocrystals by disintegration of the coarse powder.
Examples for precipitation techniques are the hydrosols (List & Sucker, 1998; Sucker & Gassmann, 1994; Gassmann et al., 1994) and the IP is owned by Sandoz, now Novartis, the product NanomorphÂ® by Soliqs/Abbott (previously Knoll/BASF) and a number of other precipitation techniques (Violante & Fischer, 1991; Thies & Muller, 1998; Kipp et al., 2003) differing in precipitation details such as use of certain stabilizers (Rasenack & Muller, 2002). In this technique the poorly water-soluble drug is dissolved in an organic solvent and the solution is added into a miscible non-solvent (aqueous solvent) under agitation leading to a sudden high supersaturation, resulting in rapid nucleation and precipitation. To avoid the formation of the microparticles, stabilizers should be added. In the case of NanomorphÂ®, amorphous drug nanocrystals are produced to further enhance dissolution velocity and solubility. Uniform nanoparticles are achieved by optimizing several parameters discussed below (Gao et al., 2008) -
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1. Stirring rate
An increase in the stirring rate reduces the particle size thus intensifying the micromixing (i.e. mixing at the molecular level) between the two phases leading to enhanced rate of diffusion of drugs between the two phases. This induces a rapid and high homogenous supersaturation and increases the number of nuclei to produce smaller drug particles (Douroumis & Fahr, 2006).
2. The ratio of antisolvent to solvent
A larger ratio of antisolvent to solvent leads to a higher supersaturation in the interface of two phases causing a rapid nucleation.
3. Drug content
A higher drug concentration increases the viscosity and hinders the diffusion between the two phases leading to a non-uniform supersaturation. Hence moderate drug content is better for the precipitation progress. On the other hand, higher drug content will increase the probability of aggregation of particles (Zhang et al., 2006).
Lower saturation solubility at a lower temperature makes the system to reach supersaturation easily. In addition the nucleating process is a process of free-energy decrease and heat release, so a lower temperature will make for the nucleation.
The precipitation technique is simple and cost effective; no expensive equipments are required, compared with milling and high-pressure homogenization technique. Furthermore, this method avoids the use of high energy like in disintegration technique, which prevents denaturation of drug due to high energy input (Zhong et al., 2005). For precipitation technique the important prerequisites that should be satisï¬ed are: a) the drug should be soluble at least in one solvent, b) the solvent should be miscible with a non-solvent and c) the solvents used in this technique should be eliminated to an acceptable level in the end products.
The primary disadvantage of most currently applied bottom-up processes is that the size of the drug crystals produced cannot be controlled adequately (Kipp, 2004; Shekunov, 2006). To sum up, the bottom up techniques are not really widely used for drug nanocrystal production.
Nowadays, the top down technologies of various milling techniques are more frequently used. There are two basic disintegration technologies for drug nanocrystals:
1. Pearl milling or ball milling and
2. High pressure homogenisation with different homogeniser types/homogenisation principles
Pearl milling techniques
This is a technique developed by Liversidge, leading to the product NanoCrystalsÂ® in 1990 (Liversidge et al., 1992). The technology uses a bead or a pearl mill to achieve particle size diminution consisting of milling chamber, milling pearls, milling motor, and a recirculation chamber. Basically, the drug, surfactant and water are ï¬lled into the milling chamber charged with milling pearls (typically made from glass, zircon oxide, or polystyrene resin); then the pearls are rotated at a high rate driven by the motor and the drug is comminuted into nanosized crystals by the high shear forces. A ï¬ne nanocrystal suspension can be obtained through a pearl milling process for hours to several days, depending on the drug hardness, quantities, and required particle size for different administration routes.
Erosion from the milling materials during the milling process is a common problem associated with this technique. To reduce the amount of impurities caused by erosion of the milling media, the milling beads are coated with highly cross-linked polystyrene resin (Bruno, 1992). Another problem is the adherence of product to the surface of the milling pearls and the surface of the mill. Despite the listed disadvantages, the pearl milling process has advantages like-drugs that are poorly soluble in both aqueous and organic media can be easily formulated into nanosuspensions, ease of scale-up and little batch-to-batch variation and flexibility in handling the drug quantity, ranging from 1 to 400 mg/mL, enabling formulation of very dilute as well as highly concentrated nanosuspensions (Patravale, 2004).
The three important technologies which are widely employed in production of nanocrystals based on homogenization principles are: Microï¬‚uidizer technology (eg., IDD-Pâ„¢ technology), Piston gap homogenization in water (eg., DissocubesÂ® technology) and in-water mixtures or in-nonaqueous media (eg., NanopureÂ® technology).
The microfluidizer technology
This technique involves frontal collision of two ï¬‚uid streams under pressures upto 1700 bar leading to generation of small particles (Bruno & Mc Ilwrick, 1999). The movement of two fluid streams under high pressure in opposite directions leads to particle collision, shear forces and also cavitation forces (Tunick et al., 2002). This method utilizes jet stream homogenizers such as the microï¬‚uidizer (Microï¬‚uidizerÂ®, Microï¬‚uidics Inc.USA) in two shapes, being either Y-type or Z-type. Surfactants are required to stabilize the desired particle size. A drawback of this method is that a relatively high number of cycles (50 to 100 passes) are necessary to sufï¬ciently reduce particle size. SkyePharma Canada Inc. (formerly RTP Inc.) uses this principle for their Insoluble Drug Delivery - Particles (IDD-Pâ„¢) technology for the production of submicron particles of poorly soluble drugs.
In 1995, Müller and colleagues developed this technology which was later acquired by SkyePharma PLC. The DissocubesÂ® technology employs piston-gap homogenizers. The technique involves dispersion of the drug powder in aqueous solution of surfactant which is then forced by a piston with pressures ranging up to 4000 bar, typically 1500 to 2000 bar through the tiny homogenization gap. The technique works on the principle that during homogenization the fracture of drug particles is brought about by cavitation, high-shear forces and the collision of the particles against each other. According to Bernoulli's law, in the homogenization gap the dynamic pressure of the fluid increases which is compensated by decrease in static pressure below the boiling point of aqueous phase at room temperature. As a result water starts boiling at room temperature, leading to the formation of gas bubbles, which implode when the suspension leaves the homogenization gap and normal air pressure of 1 bar is reached again. This phenomenon of formation and implosion of the gas bubbles is called cavitation. The implosion forces break the drug microparticles into nanoparticles. The collision of the particles at high speed also causes nanosizing of the drug.
Another approach using the piston-gap homogenizer developed and owned by PharmaSol GmbH in Berlin, registered trade name- NanopureÂ®, involves homogenization of drug particles in non-aqueous media (e.g. propylene glycol) or mixtures of water with water-miscible liquids (e.g. PEG, glycerol).
When water is the dispersion medium in the homogenization tube, the static pressure falls below the vapour pressure of water at room temperature leading to cavitation. But in this technology, dispersion media has a lower vapour pressure than water, the drop in the static pressure is not sufï¬cient to initiate cavitation or there will be very little cavitation compared to water. The remaining shear forces, particle collisions and turbulences are sufï¬cient to achieve nanoparticles implying that even without cavitation, sufficient size diminution can be achieved (Bushrab & Müller, 2003). The optional low temperature while homogenizing is advantageous for processing of temperature labile drugs (Müller, 2002).
Formulations with desired particle size can be obtained by controlling and optimization of three critical factors in the homogenization process, which includes - homogenisation pressure; number of homogenization cycles and temperature
A homogenizer can handle varying pressures, ranging from 100 to 1500 bar for most, so the effect of the homogenization pressure on the particle size should be investigated to obtain an optimized formulation. Higher homogenization pressure leads to higher velocity of the ï¬‚uid in the gap causing increased drop in static pressure with the generation of more bubbles and then higher the energy to bray the particles.
Number of homogenization cycles
For many drugs, single homogenization cycle is not sufï¬cient to comminute all particles to desired particle size even at the highest applied pressure of 1500 bar, so multiple homogenization cycles are required to break down the crystalline structure. Therefore, homogenization is often performed in ï¬ve, ten or more cycles. The number of homogenization cycles depends on the hardness of the drug, the desired particle size and the required homogeneity of the product. It is expected that at higher number of homogenization cycles, smaller particle size is obtained. The studies carried out on a model drug, RMKP 22 revealed that an inverse relationship exists between the number of homogenization cycles and the particle size (Muller & Bohm, 1998; Muller & Peters, 1998).
Temperature during the preparation of nanocrystals is an important parameter to be kept under control for thermolabile drugs. The temperature is usually found to increase in the homogenization process and this is not favourable for thermosensitive drugs. However the temperature can be reduced by placing a heat exchanger ahead of homogenizer valve, and the sample temperature can be thus maintained at about 10° C or even below.
For example, to avoid the degradation of omeprazole, the nanosuspensions were prepared at 0° C, and the samples were cooled down to 0° C between each cycle if any elevation of temperature was noted (Möschwitzer et al., 2004). Nifedipine nanosuspensions were produced using an Avestin EmulsiFlex-C5 homogenizer equipped with a heat exchanger to maintain a lower temperature (Hecq et al., 2005). Nanocrystals of ucb-35440-3, a new drug entity under investigation were formulated using high pressure homogenization for enhancement of solubility and dissolution characteristics. Investigation of in vitro dissolution characteristics showed that dissolution rate increased significantly at pH 3, 5 and 6.5 for ucb-35440-3 nanoparticles in comparison to unmilled drug. In vivo pharmacokinetic evaluation of ucb-35440-3 nanoparticles carried out on rats revealed a lower systemic exposure than unmilled compound (Hecq et al., 2006).
Lyophilized Rutin nanocrystals were prepared by high pressure homogenization and evaluated for their physicochemical properties (Mauludin et al., 2009). The lyophilized rutin nanocrystals could be redispersed completely in water and kinetic solubility was found to increase to 133 Âµg/ml. Lyophilized rutin nanocrystals dissolved completely within 15 min in water, buffer pH 1.2 and pH 6.8 in contrast to dissolution of ~ 70% of rutin raw material (rutin microcrystal) during the same time period. Thus, lyophilized rutin nanocrystals improved kinetic saturation solubility and dissolution velocity in a pronounced manner compared to rutin microcrystals.
The technique provides many advantages like ease of scale-up and little batch-to-batch variation and narrow size distribution of the nanoparticulate drug in the final product. The method allows aseptic production of nanosuspensions for parenteral administration and also enables formulation of very dilute as well as highly concentrated nanosuspensions as the method can handle a drug quantity ranging from 1 to 400 mg/mL (Krause & Muller, 2001).
Recent initiatives in Nanocrystals technology:
Nanoparticle technology has found increasing importance by pharmaceutical manufacturers. Several products have been marketed by pharmaceutical manufacturers in recent times (Table 1). Baxter, a leading pharmaceutical company, uses a precipitation step with subsequent annealing step by applying high energy, eg, high shear and/or thermal energy for its NanoEdgeâ„¢ technology (Rabinow, 2004). The subsequent homogenization preserves the particle size range obtained after the precipitation step. In addition, this 'annealing' process converts precipitated particles to crystalline material. PharmaSol uses in its Nanopure XP technology a pre-treatment step with subsequent homogenization to produce particles well below 100 nm (Möschwitzer & Müller, 2005)
A novel bottom-up process based upon freeze drying - "controlled crystallization during freeze drying", was developed by Waard et al, for the production of nanocrystalline particles. This novel process could strongly increase the dissolution behavior of fenoï¬brate (Waard et al., 2009).
Among other technologies, the supercritical ï¬‚uid methods include rapid expansion of supercritical solution (RESS), rapid expansion from supercritical to aqueous solution (RESAS), solution enhanced dispersion by the supercritical ï¬‚uids (SEDS), spray freezing into liquid (SFL), evaporative precipitation into aqueous solution (EPAS), and aerosol solvent extraction (ASES) (Müller & Bleich, 1996; Lee, 2005).
Characterization of nanocrystal formulations
The essential characterization parameters for nanocrystal/ nanocrystal suspensions are as follows:
Size and size distribution
The mean particle size and the width of particle size distribution (polydispersity index, PI) are important characterizations of nanocrystals as they govern the saturation solubility, dissolution velocity, physical stability and even biological performance of nanosuspensions and are typically analyzed by photon correlation spectroscopy (PCS) with Malvern nanosizer (Muller & Muller, 1984).
The PI is an important parameter that governs the physical stability of nanosuspensions and ranges from 0 (monodisperse particles) to 0.500 (broad distribution). The PI value should be as low as possible for the long-term stability of nanosuspensions. PCS analytical method is essentially a tool for measuring low particle size in the range of 3 nm to 3 Î¼m. This has limited the use of PCS as it cannot determine the possibility of contamination of the nanosuspension by microparticulate drugs (having particle size greater than 3 Î¼m). Therefore, to achieve a high degree of accuracy in measuring the particle size of nanocrystal formulations it is desirable to use, in addition to PCS analysis, laser diffractometry (LD). Laser diffactormetry analysis of nanosuspensions is carried out to detect and quantify the drug microparticles that might have been generated during the production process.
Laser diffractometry yields a volume size distribution and has a measuring range of 0.05-80 Î¼m and in certain instruments particle sizes up to 2000 Î¼m can be measured. Typical characterization parameters of LD are diameters 50, 90, 95, 99%, represented by D50, D90, D95 and D99, respectively (i.e. the D99 means that 99% of the volume of the particles is below the given size). It should be noted that the particle size data of a nanosuspension obtained by LD and PCS analysis are not identical as LD data are volume based and the PCS mean diameter is the light intensity weighted size.
In addition to PCS and LD, particle size analysis by the Coulter counter technique is utilized for nanosuspensions that are intended for intravenous administration. In comparison to LD that provides only a relative size distribution, the Coulter counter gives absolute data i.e. absolute number of particles per volume unit for the different size classes and hence is more efficient and appropriate technique than LD analysis for the determination of the contamination of nanosuspensions by microparticulate drugs.
If the nanosuspension contains even a small number of particles greater than 5-6 Î¼m, it can cause capillary blockade or emboli formation, as the size of the smallest blood capillary is 5-6 Î¼m. Therefore, content of microparticles in nanosuspensions need to be controlled by Coulter counter analysis.
Shape and morphology
Typically, the shape or the morphology of the nanocrystals can be determined using a transmission electron microscope (TEM) and/or a scanning electron microscope (SEM). The TEM analysis needs a wet sample of suitable concentration. When the original nanosuspension is required to be processed into dried powder, SEM analysis monitors the changes of the particle size before and after the water removal. An increase in the particles' size may occur following water removal due to agglomeration phenomenon which can be viewed through SEM. The particle interaction and agglomeration can be prevented by addition of protectants like mannitol, generally used as a cryoprotectant in lyophilization, which can recrystallize around nanocrystals during the water-removal operation. An agglomeration to a certain limit is permitted when the particle size is within an accepted range. The shape of the drug crystals depends on their crystalline structure; different crystal shapes of different drugs were viewed under SEM.
Particle charge (zeta potential)
Zeta potential is parameter that allows the prediction of physical stability of nanosuspension and is governed by both the stabilizer and the drug itself. If the particles possess enough zeta potential that provides sufï¬cient electric repulsion, or enough steric barriers providing sufï¬cient steric repulsion between each other, particle aggregation is not expected to occur. For a stable nanosuspension stabilized by electrostatic repulsion alone, a minimum zeta potential of Â±30 mV is required while the one stabilized by combined electrostatic and steric stabilization, a minimum zeta potential of Â±20 mV is desirable (Muller & Jacobs, 2002).
The assessment of the crystalline state helps in understanding the polymorphic changes that a drug might undergo when subjected to nanosizing. Additionally, preparation of nanosuspensions may generate drug particles in an amorphous state. The changes in the physical state of the drug particles as well as the extent of the amorphous fraction can be determined by X-ray diffraction analysis (Muller & Grau, 1998) and can be supplemented by differential scanning calorimetry (Shanthakumar et al., 2005).
It was reported that some drugs retained their crystalline state during homogenization, such as danazol, nifedipine, and ucb-35440-3 (Hecq et al., 2006). However, for some drugs like azithromycin, the results of DSC and X-ray showed that amorphous state was generated during homogenization (Zhang et al., 2007).
Saturation solubility and dissolution velocity
The determination of the saturation solubility and dissolution velocity help to predict any change in the in vivo performance (blood profiles, plasma peaks and bioavailability) of the drug and assess the advantages that can be achieved over conventional formulations, especially when designing the sustained-release dosage forms based on nanoparticulate drug. The dissolution velocity of drug nanosuspensions in various physiological buffers should be determined according to methods reported in the pharmacopoeia. The saturation solubility of the drug in different physiological buffers as well as at different temperatures should be assessed using methods described in the literature.
The study on the surface parameters of nanosuspensions is very crucial, particularly for the nanosuspensions to be administrated intravenously. The fate of the nanocrystals in vivo following injection, such as organ distribution, depends on its surface properties, such as surface hydrophobicity. In addition it is a relevant parameter for the interaction with cells prior to phagocytosis (Van Oss et al., 1984; Muller, 1991) and with plasma proteins (Blunk et al., 1993; Luck et al., 1997a; Luck et al., 1997b; Schmidt & Muller, 2003; Goppert & Muller, 2005).
Hydrophobic interaction chromatography has been used to determine the surface hydrophobicity (Wallis & Muller, 1993) and 2-D PAGE can be performed for quantitative and qualitative measurement of the protein adsorption after intravenous injection of nanosuspensions (Blunk et al., 1996).
Declaration of interest
Authors declare that there is no declaration of interest to this article.
Nanocrystals is a unique approach for combating poor bioavailability associated with poorly soluble drug entities. This technology offers great benefits and can be considered as a universal formulation approach for poorly soluble drugs. Production techniques like pearl milling and high pressure homogenization have been successfully employed for large scale production. Attractive properties such as increased dissolution velocity, increased saturation solubility, improved bioadhesivity have widened the application of nanocrystals for various routes. Development of stealth nanocrystals and active targeting nanocrystals modified with functionalized surface coating can be regarded as future sites in nanocrystal research.